CN101072551A - Sustained release formulation comprising bisphosphonate - Google Patents

Sustained release formulation comprising bisphosphonate Download PDF

Info

Publication number
CN101072551A
CN101072551A CNA2005800416891A CN200580041689A CN101072551A CN 101072551 A CN101072551 A CN 101072551A CN A2005800416891 A CNA2005800416891 A CN A2005800416891A CN 200580041689 A CN200580041689 A CN 200580041689A CN 101072551 A CN101072551 A CN 101072551A
Authority
CN
China
Prior art keywords
pharmaceutical composition
salt
acetate
glutamate
list
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CNA2005800416891A
Other languages
Chinese (zh)
Other versions
CN101072551B (en
Inventor
O·兰伯特
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Novartis AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis AG filed Critical Novartis AG
Publication of CN101072551A publication Critical patent/CN101072551A/en
Application granted granted Critical
Publication of CN101072551B publication Critical patent/CN101072551B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Genetics & Genomics (AREA)
  • Immunology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)
  • Steroid Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

A pharmaceutical composition for parenteral administration of a somatostatin analogue salt of aspartate, e.g. mono- or diaspartate, lactate, succinate, e.g. mono- or disuccinate acetate, glutamate, e.g. mono- or diglutamate or citrate and water forming a gelling depot system after injection in contact with the body fluid.

Description

The slow releasing preparation that comprises diphosphate
The present invention relates to composition of liquid medicine, the method that particularly comprises the depot formulation of somatostatin analogs and prepare described depot formulation.
The typically non-intestinal of depot formulation is used.The somatostatin depot formulation is can be by small size pin subcutaneous or intramuscular injection is used or be placed on accessible tissue site by intubate uses.But it may be unusual pain that non-intestinal is used, particularly if desired during duplicate injection.In addition, the depot formulation that forms solid implant after using and inject with liquid form in vivo may have difficulties.Usually, beginning process of setting and cause that pin stops up in the syringe before injection.In addition, these depot formulations can comprise polymer or polymeric blends, and this polymer or polymeric blends must be dissolved in the organic solvent, and for example it can comprise the organic solvent more than 50%.If organic solvent is present in the injection solution agent, it may cause serious tissue stimulation or necrosis at implantation site.
EP 779 805 provides pharmaceutical composition, and this pharmaceutical composition comprises soluble peptide salt (it will contact with body fluid and form gel) and accounts for composition weight pharmaceutically suitable carrier of 30% at the most.The peptide of describing among the EP 779805 is somatostatin or somatostatin analogs, for example Lanreotide (lanreotide).
Surprisingly, have been found that and use compositions can obtain favourable non-intestinal somatostatin depot formulation that said composition comprises the Yan Heshui (pH 3-7) of somatostatin analogs, and do not use polymer and not with an organic solvent.
One aspect of the present invention provides and has been used for the pharmaceutical composition that non-intestinal is used, this pharmaceutical composition comprises the Yan Heshui of somatostatin analogs, described salt is aspartate (for example single or two aspartates), glutamate, Glu (for example single or two glutamate, Glus) or succinate (for example list or disuccinate), lactate, acetate or citrate, and this pharmaceutical composition contacts the formation gelling with body fluid and stores the storehouse after injection.The salt of somatostatin analogs salt: the proportion of alkali can provide the dissolubility of the salt of somatostatin analogs for 0.1-2 and its.The pH of pharmaceutical composition is between about 3.0 and 7.0, preferably between 4.0 and 6.0 and more preferably between about 4.0 and 5.0.Optional said composition can comprise a certain amount of pharmaceutically acceptable buffer agent pH is stabilized between about 3.0 and 7.0, preferably between about 4.0 and 6.0, most preferably between 4.0 and 5.0.
On the other hand, the invention provides and be used for the pharmaceutical composition that non-intestinal is used, this pharmaceutical composition comprises the Yan Heshui of somatostatin analogs, described salt is aspartate (for example single or two aspartates), glutamate, Glu (for example single or two glutamate, Glus), lactate, succinate (for example list or disuccinate), acetate or citrate, pH is between about 3.0 and 7.0, and this pharmaceutical composition contacts the formation gelling with body fluid and stores the storehouse after injection.
The compositions of pH between about 3.0 and 7.0 provide good dissolubility and therefore the present composition can store the time of prolongation and not produce precipitation.By injection compositions is applied to the patient, wherein compositions after interacting with patient's body fluid rather than before begin to form gelling and store the storehouse.Go through the time cycle of prolongation, this gelling storage storehouse discharges the salt of somatostatin analogs in patient's body, and described salt is aspartate, lactate, succinate, acetate, glutamate, Glu or citrate.
On the other hand, the invention provides the method for preparing depot formulation, this method is undertaken by following steps:
I) salt of somatostatin analogs is soluble in water, described salt is aspartate (for example single or two aspartates), lactate, succinate (for example list or disuccinate), acetate, glutamate, Glu (for example single or two glutamate, Glus) or citrate
The ii) optional pH that adds buffer agent with stabilizing solution, and optional
Iii) solution is filled in the syringe.
On the other hand, the invention provides the method for preparing depot formulation, this method is undertaken by following steps:
I) salt of somatostatin analogs is soluble in water, described salt is aspartate (for example single or two aspartates), lactate, succinate (for example list or disuccinate), acetate, glutamate, Glu (for example single or two glutamate, Glus) or citrate, its pH is between 3.0 and 7.0
The ii) optional pH that adds buffer agent with stabilizing solution, and optional
Iii) solution is filled in the syringe.
The present invention relates to the salt of somatostatin analogs, described salt is aspartate (for example single or two aspartates), lactate, succinate (for example list or disuccinate), acetate, glutamate, Glu (for example single or two glutamate, Glus) or citrate.
Somatostatin is a tetradecapeptide, and its structure is
Figure A20058004168900061
The somatostatin analogs of special concern has for example been described in WO 97/01579 and WO 97/25977.Described somatostatin analogs comprises the aminoacid sequence of formula I
-(D/L)Trp-Lys-X 1-X 2-
X wherein 1Be formula (a) or (b) group
Figure A20058004168900062
R wherein 1Be the optional phenyl that replaces, wherein substituent group can be halogen, methyl, ethyl, methoxy or ethoxy.
R 2Be-Z 1-CH 2-R 1,-CH 2-CO-O-CH 2-R 1,
Figure A20058004168900063
Or
Figure A20058004168900064
Z wherein 1Be O or S, and
X 2Be C αHave the a-amino acid of aromatic moieties on the side chain or be selected from following aminoacid unit: Dab, Dpr, Dpm, His, (Bzl) HyPro, thienyl-Ala, cyclohexyl-Ala and the tert-butyl group-Ala, the residue Lys of described sequence is corresponding to the residue Lys of natural somatostatin-14 9
The applied somatostatin analogs of this paper refers to straight chain or the cyclic peptide derived from naturally occurring somatostatin-14, it comprises formula I sequence, and wherein one or more aminoacid unit are left in the basket and/or are replaced by one or more other amino acid groups and/or wherein one or more functional groups are replaced by one or more other functional groups and/or one or more group is replaced by other isostere group of or some in addition.Usually, all modified derivatives of natural somatostatin-14 contained in term, and it comprises the sequence with following formula I, and the binding affinity of the somatostatin receptor hypotype of itself and at least a hereinafter definition is in the nM scope.
8 to 11 residues that preferred somatostatin analogs is a wherein somatostatin-14 are by the displaced chemical compound of formula I sequence of above definition.
More preferably somatostatin analogs is above disclosed chemical compound, and this chemical compound comprises six peptide units, and 3 to 6 residues of described six peptide units comprise formula I sequence.Preferred especially somatostatin six peptides, wherein 1 and 2 of six peptide units residue can be that (for example A.S.Dutta is at Small Peptides, Vol.19,292-354 for any residue as known in the art, Elsevier, disclosed in 1993) or as the Phe of somatostatin-14 6And/or Phe 7Substituent group.
More particularly somatostatin analogs is that wherein six peptide units are cyclic chemical compounds, for example has the chemical compound of direct peptide bond between the alpha-amido of the alpha-carbonyl of 6 residues and 1 residue.
Lys in the formula I sequence, X 1And X 2Has the L-configuration.Trp can be D-or L-configuration.Preferred Trp has D-form.
X 1Be preferably formula (a) and (b) residue, R 2Be preferably
-Z 1-CH 2-R 1Or
Figure A20058004168900071
Work as X 2C αWhen comprising aromatic moieties on the side chain, it can suitably be natural or the non-natural a-amino acid, for example Phe, Tyr, Trp, Nal, Pal, benzothienyl-Ala, Tic and thyronine, preferably Phe or Nal, more preferably Phe.X 2Be preferably C αThe a-amino acid that has aromatic moieties on the side chain.
Work as R 1During for the phenyl that replaces, its can be suitably for example at the ortho position and/or para-position replaced by halogen, methyl, ethyl, methoxy or ethoxy.More preferably R 1Be unsubstituted phenyl.Z 1Be preferably O.
Representative compounds of the present invention is formula (II) chemical compound for example
Figure A20058004168900072
Wherein
X 1And X 2As above definition,
A be selected from following residue of divalent: Pro,
Figure A20058004168900081
Figure A20058004168900082
Figure A20058004168900083
Figure A20058004168900085
Figure A20058004168900086
With-NR 4-CH 2-CO-
R wherein 3Be NR 8R 9-C 2-6Alkylidene, guanidine radicals-C 2-6Alkylidene or C 2-6Alkylidene-COOH, R 3aBe H, C 1-4Alkyl or have R independently 3One of implication, R 3bBe H or C 1-4Alkyl, R aBe OH or NR 5R 6, R bFor-(CH 2) 1-3-or-CH (CH 3)-, R 4Be H or CH 3, R 4aOptional is cyclosubstituted benzyl, R 5And R 6Be H, C independently of one another 1-4Alkyl, omega-amino--C 1-4Alkylidene, ω-hydroxyl-C 1-4Alkylidene or acyl group, R 7Be direct key or C 1-6Alkylidene, R 8And R 9Be H, C independently of one another 1-4Alkyl, ω-hydroxyl-C 2-4Alkylidene, acyl group or CH 2OH-(CHOH) c-CH 2-(wherein c is 0,1,2,3 or 4), or R 8And R 9Form heterocyclic radical with the nitrogen-atoms that they connected, this heterocyclic radical can comprise other hetero atom, and R 11Optional for cyclosubstituted benzyl ,-(CH 2) 1-3-OH, CH 3-CH (OH)-or-(CH 2) 1-5-NR 5R 6, and
ZZ aBe natural or non-natural a-amino acid unit.
ZZ aCan have D-or L-configuration.Work as ZZ aDuring for natural or non-natural a-amino acid unit, it can suitably be for example Thr, Ser, Ala, Val, Ile, Leu, Nle, His, Arg, Lys, Nal, Pal, Tyr, Trp, optional cyclosubstituted Phe or N α-benzyl-Gly.Work as ZZ aDuring for Phe, its phenyl ring can be by for example NH 2, NO 2, CH 3, OCH 3Or halogen replaces preferred para-orientation.Work as ZZ aDuring for Phe, its phenyl ring is preferably unsubstituted.
When A comprises the Pro amino acid residue, any substituent group that exists on the proline ring (R for example 3-NH-CO-O-etc.) preferably at 4.The proline residue of this replacement can exist with the cis form, for example
Figure A20058004168900091
Also can exist with trans forms.Each single geometric isomer and composition thereof is a chemical compound of the present invention.
When A is
NR wherein 8R 9Form heterocyclic radical, this group can be aromatics or saturated and can comprise a nitrogen-atoms or a nitrogen-atoms and be selected from second hetero atom of nitrogen and oxygen.Preferred heterocyclic radical is for example pyridine radicals or morpholino.C in this residue 2-6Alkylidene is preferred-CH 2-CH 2-.
Among the A as R 5, R 6, R 8And R 9Any acyl group can be R for example 12CO-, wherein R 12Be H, C 1-4Alkyl, C 2-4Alkenyl, C 3-6Cycloalkyl or benzyl are preferably methyl or ethyl.R in A 4aOr R 11When being cyclosubstituted benzyl, phenyl ring can be as above ZZ aDescribed in be substituted.
The formula III chemical compound of preferred especially free form, salt form or protection form
Figure A20058004168900093
Being configured as of C-2 (R) or (S) or their mixture wherein, and
Wherein R is NR 10R 11-C 2-6Alkylidene or guanidine radicals-C 2-6Alkylidene, and R 10And R 11Be H or C independently of one another 1-4Alkyl, it synthesizes can be as the carrying out of describing among for example WO 2002/10192 (it incorporates this paper into as a reference).
Prepare salt by the method for describing among for example WO 2002/10192 (it incorporates this paper into as a reference).
Preferred R is NR 10R 11-C 2-6Alkylidene.Preferred formula II chemical compound is that wherein R is free form, the salt form of 2-amino-ethyl or is protected the formula II chemical compound of form, i.e. ring [{ 4-(NH 2-C 2H 4-NH-CO-O-) Pro}-Phg-DTrp-Lys-Tyr (4-Bzl)-Phe] (this paper middle finger compd A) and ring [{ 4-(NH 2-C 2H 4-NH-CO-O-) Pro}-DPhg-DTrp-Lys-Tyr (4-Bzl)-Phe].Phg refers to-HN-CH (C 6H 5)-CO-and Bzl refer to benzyl.
The salt of the present invention of protection form is corresponding to somatostatin analogs, and at least one amino is protected and forms formula II chemical compound by deprotection in this somatostatin analogs, and preferred physiology goes up removable.The amino protecting group that is fit to is for example " Protective Groups inOrganic Synthesis ", T.W.Greene, J.Wiley﹠amp; Sons NY (1981), disclosed among the 219-287, its content is incorporated this paper into as a reference.The example of this type of amino protecting group is an acetyl group.
The present composition can comprise buffer agent.The buffer agent that is fit to includes but not limited to acetate buffer, lactate buffer agent, glycine buffer and tartrate buffer agent.The concentration of buffer agent can be about 5mM to 30mM, preferably about 10mM to 25mM.
On the other hand, the invention provides the pharmaceutical composition of viscous liquid form, said composition can be by the pin injector to inject of 18G to 25G, for example 20G.By (its viscosity is 1 to 10 behind the 0.2 μ M filter sterilising filtration 4MPa.s) or sterilising filtration and remove by evaporation or distillation and to desolvate that (its viscosity is 10 in the back 2To 10 6MPa.s), solution can be placed syringe.Solvent is removed and can be carried out after solution is placed syringe.
Solution in the syringe can by under pin (for example pin of the 20G) epidermis, intramuscular, corium down or peritoneal injection go in the body or to place accessible tissue site by intubate.In case this solution contacts with patient's body fluid in position, just formed gelling storage storehouse.The fluid composition that non-intestinal is used can be filled in the syringe, and preferred pre-filled syringe can provide together with operation instructions.
On the other hand, the invention provides the slow release depot formulation of medical active agent.The implant that is injected into back formation in the body can be gone through the time cycle release bioactive agent of prolongation.The scope of release period can be 1 to 90 days at the most, for example 1 to 60 days at the most, and for example 30 to 60 days.
The present composition is used for the treatment of the known indication of sp act agent.The present composition that comprises the salt (described salt is aspartate, lactate, succinate, acetate, glutamate, Glu or citrate) of somatostatin analogs can be used for following indication:
A) be used to prevent or treat have comprise the excessive of excessive GH-secretion and/or IGF-1 or with excessive GH-secretion and/or the excessive relevant etiologic etiological obstacle of IGF-1, for example treat acromegaly and treatment I type or type ii diabetes, their complication particularly, angiopathy for example, diabetic proliferative retinopathy becomes, diabetic macular edema, nephropathy, neuropathy and dawn phenomenon, and other the dysbolismus relevant with glucagon release with insulin, obesity for example, morbid obesity or hypothalamic obesity or hyperinsulinemia (hyperinsulinemic) obesity for example
B) be used for the treatment of enterocutaneous fistula and pancreas skin fistula, irritable bowel syndrome, inflammatory diseases (Graves disease for example, inflammatory bowel, psoriasis or rheumatoid arthritis), multicystic kidney disease, dumping syndrome, the watery diarrhea syndrome, the relevant diarrhoea of AIDS-, the inductive diarrhoea of chemotherapy, acute or chronic pancreatitis and gut hormone secreting tumor (GEP tumor for example, vasoactive intestinal polypeptide tumor for example, glucagonoma, insulinoma, carcinoid etc.), lymphocyte pernicious (for example lymphoma or leukemia), hepatocarcinoma and gastrointestinal hemorrhage (for example varicosis esophagorrhagia)
C) be used for prevention or treatment angiogenesis, above-mentioned inflammatory disorder comprise inflammatory eye disease, macular edema, for example cystoid macular edema, spy send out property cystoid macular edema, exudative age-related macular degeneration, choroid neovascularization associated disorders and proliferative retinopathy
D) be used for prevention or opposing graft angiopathy, for example allograft or xenograft angiopathy, for example at organ transplantation (heart for example, lung, the cardiopulmonary associating, liver, kidney or pancreas are transplanted) in the graft artery atherosis, perhaps be used for prevention or treatment vein transplantation thing is narrow, vascular occlusion behind restenosis and/or the blood vessel injury, this blood vessel injury is by for example catheterization process or blood vessel scratch process percutaneous transluminal angio plasty for example, laser therapy or other invasive process of destroying tunica intima or endothelium integrity cause
E) being used for the treatment of the somatostatin receptor expresses or accumulates for example pituitary tumor (for example hypercortisolism) of tumor, the gastrointestinal pancreas, carcinoid, the central nervous system, mammary gland, prostate (comprising the intractable carcinoma of prostate that hormone raises), ovary or colon tumor, small cell lung cancer, pernicious intestinal obstruction, pheochromocytoma, renal carcinoma, skin carcinoma, neuroblastoma, pheochromocytoma, medullary thyroid carcinoma, myeloma, lymphoma, Huo Qijin and non-Hodgkin lymphoma, osteoma and transfer thereof, and autoimmune or inflammatory disorder, for example rheumatoid arthritis, Graves disease or other inflammatory eye disease.
The present composition is preferred for treating acromegaly, carcinoid and/or hypercortisolism.
The activity of fluid composition of the present invention and feature can illustrate in standard clinical tests or animal experiment.
The effect that the suitable dosage of the present composition will for example depend on disease to be treated (for example repellence disease type), used medicine, expection certainly is with method of application and different.
The present composition for the salt that comprises somatostatin analogs (described salt is aspartate, lactate, succinate, acetate, glutamate, Glu or citrate), can be by the following acquisition satisfactory result of using: for example non-intestinal be used, dosage is that about 0.1mg is to about 100mg, the preferred about 3mg/ pin/moon to about 60mg/ pin/moon or about 0.01mg are to about 4mg, it is preferred that the 0.1mg/kg the weight of animals/moon, disposable employed or divided dose was used to 1mg/kg the weight of animals/moon.Therefore, patient's the moon dosage that is fit to is the salt (described salt be aspartate, lactate, succinate, acetate, glutamate, Glu or citrate) of about 0.1mg to about 80mg somatostatin analogs.
The invention provides the salt of somatostatin analogs and the simple pharmaceutical composition of water, described salt is aspartate (for example single or two aspartates), lactate, succinate (for example list or disuccinate), acetate, glutamate, Glu (for example single or two glutamate, Glus) or citrate, salt wherein: the alkali proportion is 0.1 to 2, the pH of definition is 3.0 to 7.0, preferred about 4.0 to 6.0, more preferably from about 4.0 to 5.0.Saline and alkaline proportion 0.1 to 2 provides the dissolubility of somatostatin analogs salt under given pH and formation and the therefore change of the environment pH of generation that contacts postprecipitation and storage storehouse with body fluid.Can stablize pH with buffer agent.The preparation method for compositions is simple, and it is by being added to water in the salt of somatostatin analogs.At pH about 4.0 to 6.0 o'clock, compositions table revealed good dissolubility and has therefore avoided for example producing precipitation in pre-syringe of filling or pin stops up.There is not to use the organic solvent that may produce serious side effects in site of administration.
Below only the mode of the embodiment by method and composition of the present invention is described.
Embodiment 1
Raw material Weight g The weight that needs Actual weight
Somatostatin two aspartates 58.8235 0.8g 0.8g
Water for injection (WFI) 100 1.36mL 1.36mL
By 0.8g somatostatin two aspartates and 1.36mL water for injection being mixed with the solution of 2mL pharmaceutical composition of the present invention.
Embodiment 2
The release profiles of drug products in rabbit that contains the compositions that provides among the embodiment 1.Non-intestinal is injected said composition and was gathered the several blood sample to measure somatostatin two aspartates during 2 months.
Somatostatin in the rabbit plasma
Figure A20058004168900131
Time [my god]
Embodiment 3
Raw material The weight that needs Actual weight
The somatostatin disuccinate 1.0g 0.999g
Water for injection (WFI) 1.6mL 1.6mL
By 0.999g somatostatin disuccinate and 1.6mL water for injection being mixed with the disuccinic acid salt form of pharmaceutical composition of the present invention.
Embodiment 4
Raw material The weight that needs Actual weight
Somatostatin two glutamate, Glus 0.916g 0.916g
Water for injection (WFI) 1.44mL 1.44mL
By 0.916g somatostatin two glutamate, Glus and 1.44mL water for injection being mixed with two glutamate, Glu forms of pharmaceutical composition of the present invention.
Embodiment 5
The release profiles of drug products in rabbit that contains the compositions that provides in embodiment 3 and 4.Non-intestinal is injected said composition and was gathered the several blood sample to measure somatostatin disuccinate and somatostatin two glutamate, Glus during 2 months.
Figure A20058004168900141

Claims (16)

1. the pharmaceutical composition that non-intestinal is used, this pharmaceutical composition comprises the Yan Heshui of somatostatin analogs, described salt is single or two aspartates, list or two glutamate, Glus, list or disuccinate, acetate or citrate, and this pharmaceutical composition contacts the formation gelling with body fluid and stores the storehouse system after injection.
2. the pharmaceutical composition that non-intestinal is used, this pharmaceutical composition comprises the Yan Heshui of somatostatin analogs, described salt is single or two aspartates, list or two glutamate, Glus, lactate, list or disuccinate, acetate or citrate, pH is between 3.0 and 7.0, and this pharmaceutical composition contacts the formation gelling with body fluid and stores the storehouse system after injection.
3. claim 1 or 2 pharmaceutical composition, wherein the salt of somatostatin analogs has salt: the proportion of alkali is 0.1 to 2.
4. according to the pharmaceutical composition of claim 1, its pH is between about 4.0 and 6.0.
5. according to the pharmaceutical composition of any aforementioned claim, its pH is between about 4.0 and 5.0.
6. according to the pharmaceutical composition of any aforementioned claim, it comprises a certain amount of pharmaceutically acceptable buffer agent to provide pH between about 3 and 7.
7. according to the pharmaceutical composition of claim 6, its pH is between about 4.0 and 5.0.
8. according to the pharmaceutical composition of claim 6 and 7, wherein pharmaceutically acceptable buffer agent is selected from least a in the following buffer agent: acetate buffer, tartrate buffer agent, glycine buffer and lactate buffer agent.
9. according to the pharmaceutical composition of claim 6 to 8, wherein pharmaceutically acceptable buffer agent is an acetate buffer.
10. according to the pharmaceutical composition of claim 9, the concentration of wherein used acetate buffer is about 10mM to 25mM.
11. pharmaceutical composition according to any aforementioned claim, wherein said gelling storage storehouse system goes through time cycle lasting salt that discharges somatostatin analogs in patient's body of 1 to 90 day prolongation, and described salt is aspartate, lactate, succinate, acetate, glutamate, Glu or citrate.
12. the pharmaceutical composition of claim 11, wherein said gelling storage storehouse system goes through time cycle lasting salt that discharges somatostatin analogs in patient's body of 1 to 60 day prolongation, and described salt is aspartate, lactate, succinate, acetate, glutamate, Glu or citrate.
13. according to the pharmaceutical composition of any aforementioned claim, its viscosity is 1 to 10 6MPas.
14. pre-filled syringe, this syringe comprise the compositions and the operation instructions of any aforementioned claim.
15. preparation is according to the method for pharmaceutical composition any in the claim 1 to 13, this method comprises
I) salt of somatostatin analogs is soluble in water, described salt is single or two aspartates, list or two glutamate, Glus, lactate, list or disuccinate, acetate or citrate,
The ii) optional buffer agent that adds pharmaceutically acceptable amount, and optional
Iii) solution is filled in the syringe.
16. preparation is according to the method for pharmaceutical composition any in the claim 1 to 13, this method comprises
I) salt of somatostatin analogs is soluble in water, described salt is single or two aspartates, list or two glutamate, Glus, lactate, list or disuccinate, acetate or citrate,
The buffer agent that ii) adds pharmaceutically acceptable amount to be obtaining pH between 3.0 and 7.0, and optional
Iii) solution is filled in the syringe.
CN2005800416891A 2004-12-22 2005-12-20 Sustained release formulation comprising bisphosphonate Active CN101072551B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB0428151.5 2004-12-22
GBGB0428151.5A GB0428151D0 (en) 2004-12-22 2004-12-22 Organic compounds
PCT/EP2005/013703 WO2006066868A2 (en) 2004-12-22 2005-12-20 Sustained release formulation comprising bisphosphonate

Publications (2)

Publication Number Publication Date
CN101072551A true CN101072551A (en) 2007-11-14
CN101072551B CN101072551B (en) 2013-04-24

Family

ID=34113101

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2005800416891A Active CN101072551B (en) 2004-12-22 2005-12-20 Sustained release formulation comprising bisphosphonate

Country Status (19)

Country Link
US (2) US20100029550A1 (en)
EP (1) EP1830806B1 (en)
JP (1) JP4977622B2 (en)
KR (1) KR101335757B1 (en)
CN (1) CN101072551B (en)
AR (1) AR051803A1 (en)
AU (1) AU2005318454B2 (en)
BR (1) BRPI0519209A2 (en)
CA (1) CA2585116C (en)
ES (1) ES2515097T3 (en)
GB (1) GB0428151D0 (en)
GT (1) GT200500358A (en)
MX (1) MX2007007572A (en)
PE (1) PE20060769A1 (en)
PL (1) PL1830806T3 (en)
PT (1) PT1830806E (en)
RU (1) RU2395274C2 (en)
TW (1) TW200637612A (en)
WO (1) WO2006066868A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105392470A (en) * 2013-07-09 2016-03-09 益普生药业公司 Pharmaceutical composition for a sustained release of lanreotide

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0428151D0 (en) * 2004-12-22 2005-01-26 Novartis Ag Organic compounds
JP5331817B2 (en) 2007-12-03 2013-10-30 イタルファルマコ ソシエタ ペル アチオニ Novel non-selective somatostatin analogues
EP2067786A1 (en) 2007-12-07 2009-06-10 ITALFARMACO S.p.A. Novel non selective analogs of somatostatin
JP6029472B2 (en) 2010-01-13 2016-11-24 イプセン ファルマ ソシエテ パール アクシオン サンプリフィエＩｐｓｅｎ Ｐｈａｒｍａ Ｓ．Ａ．Ｓ． Method for producing a pharmaceutical composition for sustained release of a somatostatin analogue (analog)
US8535544B2 (en) 2010-07-26 2013-09-17 International Business Machines Corporation Structure and method to form nanopore
WO2013131879A1 (en) 2012-03-07 2013-09-12 Novartis Ag New application for pasireotide
WO2018048609A1 (en) * 2016-09-06 2018-03-15 Monell Chemical Senses Center Method of regulating immunity in the intestines
EP3592358A4 (en) * 2017-03-09 2020-12-16 Corcept Therapeutics, Inc. Use of glucocorticoid receptor modulators in the treatment of catecholamine-secreting tumors
GR1009814B (en) * 2019-07-29 2020-09-11 Φαρματεν Α.Β.Ε.Ε. Pharmaceutical composition comprising a somatostatin peptide analogue
AU2022390573A1 (en) * 2021-11-22 2024-05-16 SpecGx LLC Injectable sustained release pharmaceutical composition

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0083305B1 (en) * 1981-12-24 1985-07-10 Ciba-Geigy Ag Cyclic octapeptides and pharmaceutical compositions thereof, and processes for their production and use
PH30995A (en) * 1989-07-07 1997-12-23 Novartis Inc Sustained release formulations of water soluble peptides.
US5595760A (en) * 1994-09-02 1997-01-21 Delab Sustained release of peptides from pharmaceutical compositions
MY147327A (en) 1995-06-29 2012-11-30 Novartis Ag Somatostatin peptides
GB9601120D0 (en) 1996-01-19 1996-03-20 Sandoz Ltd Organic compounds
US20020111603A1 (en) * 1996-12-02 2002-08-15 Societe De Conseils De Recherches Et D'application Device for local administration of solid or semi-solid formulations and delayed-release formulations for proposal parental administration and preparation process
ES2256898T3 (en) 1996-12-20 2006-07-16 Alza Corporation COMPOSITION OF GEL AND PROCEDURES.
FR2776520B1 (en) * 1998-03-25 2000-05-05 Sod Conseils Rech Applic NOVEL PHARMACEUTICAL COMPOSITIONS FOR THE SUSTAINED RELEASE OF PEPTIDES AND THEIR PREPARATION PROCESS
GB0018891D0 (en) * 2000-08-01 2000-09-20 Novartis Ag Organic compounds
US7098305B2 (en) * 2001-09-06 2006-08-29 Ardana Bioscience Limited Sustained release of microcrystalline peptide suspensions
ATE432689T1 (en) * 2002-03-04 2009-06-15 Ipsen Pharma SUSTAINED RELEASE DRUG FORMULATIONS CONTAINING A CARRIER PEPTIDE
GB0300095D0 (en) 2003-01-03 2003-02-05 Novartis Ag Organic compounds
GB0428151D0 (en) * 2004-12-22 2005-01-26 Novartis Ag Organic compounds
JP5721624B2 (en) * 2008-07-08 2015-05-20 ノバルティス アーゲー Use of pasireotide for the treatment of endogenous hyperinsulinemia hypoglycemia

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105392470A (en) * 2013-07-09 2016-03-09 益普生药业公司 Pharmaceutical composition for a sustained release of lanreotide

Also Published As

Publication number Publication date
AU2005318454A1 (en) 2006-06-29
US20100029550A1 (en) 2010-02-04
PT1830806E (en) 2014-11-24
KR20070090942A (en) 2007-09-06
CA2585116C (en) 2014-05-20
BRPI0519209A2 (en) 2009-01-06
US9303067B2 (en) 2016-04-05
TW200637612A (en) 2006-11-01
WO2006066868A2 (en) 2006-06-29
AR051803A1 (en) 2007-02-07
JP2008524290A (en) 2008-07-10
MX2007007572A (en) 2007-07-24
CN101072551B (en) 2013-04-24
EP1830806B1 (en) 2014-09-03
EP1830806A2 (en) 2007-09-12
GT200500358A (en) 2006-08-07
GB0428151D0 (en) 2005-01-26
PE20060769A1 (en) 2006-09-28
CA2585116A1 (en) 2006-06-29
RU2007128101A (en) 2009-01-27
WO2006066868A3 (en) 2006-10-12
RU2395274C2 (en) 2010-07-27
KR101335757B1 (en) 2013-12-02
US20150038414A1 (en) 2015-02-05
JP4977622B2 (en) 2012-07-18
AU2005318454B2 (en) 2009-08-20
ES2515097T3 (en) 2014-10-29
PL1830806T3 (en) 2015-03-31

Similar Documents

Publication Publication Date Title
CN101072551B (en) Sustained release formulation comprising bisphosphonate
JP5469810B2 (en) A pharmaceutical composition comprising polyethylene glycol having a molecular weight of less than 600 Daltons
KR101233892B1 (en) Microparticles comprising somatostatin analogues
EP2478011B1 (en) Fluorinated ghrh antagonists
JP3784418B2 (en) Combination of somatostatin analog and rapamycin
JPS58116421A (en) Insulin releasing agent
CN101983068B (en) Novel n-and c-terminal substituted antagonistic analogs of gh-rh
CN101378775B (en) Combination of somatostatin-analogs with different selectivity for human somatostatin receptor subtypes
KR20060088875A (en) Antagonistic analogs of gh-rh (2003)
NO330706B1 (en) Pharmaceutical composition comprising somatostatin analogue and tartaric acid and their use
AU2002363248B2 (en) Method of administering a Thymosin alpha 1 peptide
US20160166652A1 (en) Novel n- and c-terminal substituted antagonistic analogs of gh-rh

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C56 Change in the name or address of the patentee

Owner name: NOVARTIS CO., LTD.

Free format text: FORMER NAME: NOVARTIS AG

CP01 Change in the name or title of a patent holder

Address after: Basel

Patentee after: Novartis Ag

Address before: Basel

Patentee before: Novartis AG